Crystalline forms of mnk inhibitors

ABSTRACT

The crystalline compounds of the present application are inhibitors of Mnk and finds utility in any number of therapeutic applications, including but not limited to treatment of inflammation and various cancers.

CROSS-REFERENCE OF RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/749,820, filed Oct. 24, 2018, which is herein incorporated byreference.

FIELD

The present invention generally relates to crystalline forms of acompound having activity as an inhibitor of MAP kinase-interactingkinase (Mnk), for example Mnk1 and Mnk2, as well as to pharmaceuticalcompositions and processes for making the inventive compound, which isutilized as a therapeutic agent for the treatment of Mnk dependentdiseases, including the treatment of cancer.

BACKGROUND

Eukaryotic initiation factor 4E (eIF4E) is a general translation factorbut it has the potential to enhance preferentially the translation ofmessenger RNAs (mRNAs) that lead to the production ofmalignancy-associated proteins. This selectivity may relate to anincreased requirement for eIF4E and its binding partners for thetranslation of mRNAs containing extensive secondary structure in their5′-untranslated regions (5′-UTRs). Elevated levels of eIF4E have beenfound in many types of tumors and cancer cell lines including cancers ofthe colon, breast, bladder, lung, prostate, gastrointestinal tract, headand neck, Hodgkin's lymphomas and neuroblastomas.

The PI3K (phosphoinositide 3-kinase)/PTEN (phosphatase and tensinhomologue deleted on chromosome ten)/Akt/mTOR (mammalian target ofrapamycin) pathway is important in regulating mRNA translation of genesthat encode for pro-oncogenic proteins and activated mTORC1 signaling ina high proportion of cancers, these kinases have been actively pursuedas oncology drug targets. A number of pharmacological inhibitors havebeen identified, some of which have reached advanced clinical stages.However, it has recently become clear that the mTOR pathway participatesin a complicated feedback loop that can impair activation of Akt.

Mnk1 and Mnk2 are threonine/serine protein kinases and specificallyphosphorylate serine 209 (Ser209) of eIF4E within the eIF4F complex.While Mnk activity is necessary for eIF4E-mediated oncogenictransformation, it is dispensable for normal development.Pharmacologically inhibiting Mnks thus presents an attractivetherapeutic strategy for cancer.

Despite increased understanding of Mnk structure and function, littleprogress has been made with regard to the discovery of pharmacologicalMnk inhibitors and relatively few Mnk inhibitors have been reported:CGP052088 (Tschopp et al., Mol Cell Biol Res Commun. 3(4):205-211,2000); CGP57380 (Rowlett et al., Am J Physiol Gastrointest LiverPhysiol. 294(2):G452-459, 2008); and Cercosporamide (Konicek et al.,Cancer Res. 71(5):1849-1857, 2011). These compounds, however, havemainly been used for the purpose of Mnk target validation. Morerecently, investigators have proposed further compounds for treatingdiseases influenced by the inhibition of kinase activity of Mnk1 and/orMnk2, including, for example, the compounds disclosed in InternationalPatent Application no. WO/2017/075394; U.S. Pat. Nos. 9,382,248;9,669,031; and 9,814,718.

Accordingly, while advances have been made in this field there remains asignificant need in the art for compounds and pharmaceuticallyacceptable compositions that effectively inhibit Mnk kinase activity,particularly with regard to Mnk's role in the regulation of cancerpathways, as well as for associated composition and methods. The presentinvention fulfills this need and provides further related advantages.

SUMMARY

The present invention is directed to crystalline forms of a compoundthat inhibit or modulate the activity of Mnk. The present invention alsois directed to pharmaceutically acceptable compositions containing sucha compound and associated methods for treating conditions that wouldbenefit from Mnk inhibition, such as cancer.

In one embodiment the invention is directed to a crystalline compoundof:

or stereoisomers, tautomers, or solvates thereof.

In another embodiment, the invention is directed to a crystallinecompound wherein the compound has an X-ray powder diffraction patternwith characteristic peaks expressed in values of degrees 2Θ at about8.07; about 10.81; about 14.68; and about 22.07±0.2.

In an embodiment, the crystalline solid of the compound has an X-raypowder diffraction pattern with characteristic peaks expressed in valuesof degrees 2Θ at about 8.07; about 10.81; about 14.68; about 16.69;about 17.34; and about 22.07±0.2.

In another embodiment, the crystalline solid of the compound has anX-ray powder diffraction pattern with characteristic peaks expressed invalues of degrees 2Θ at about 8.07; about 10.81; about 12.00; about12.37; about 13.79; about 14.68; about 15.39; about 16.19; about 16.69;about 17.34; about 18.89; about 20.26; about 21.15; about 21.30; about21.77; about 22.07; about 22.84; about 23.49; about 24.40; about 24.90;about 25.34; about 25.75; about 26.12; about 26.54; about 27.16; about27.48; about 28.06; about 28.76; about 29.04; about 29.26; and about29.59±0.2.

In a further embodiment, the crystalline solid has an X-ray powderdiffraction pattern substantially as shown in FIG. 1.

The present invention also provides a pharmaceutical compositioncomprising (i) a therapeutically effective amount of at least onecrystalline solid according to the present application or astereoisomer, tautomer, or solvate thereof; (ii) in combination with apharmaceutically acceptable carrier, diluent or excipient.

Also provided by the present invention is a method for attenuating orinhibiting the activity of Mnk in at least one cell overexpressing Mnk,comprising contacting the at least one cell with a compound according tothe present application or a stereoisomer, tautomer, or solvate thereof.

According to the inventive method at least one cell is a colon cancercell, a gastric cancer cell, a thyroid cancer cell, a lung cancer cell,a leukemia cell, a B-cell lymphoma, a T-cell lymphoma, a hairy celllymphoma, Hodgkin's lymphoma cell, non-Hodgkin's lymphoma cell,Burkitt's lymphoma cell, a pancreatic cancer cell, a melanoma cell, amultiple melanoma cell, a brain cancer cell, a CNS cancer cell, a renalcancer cell, a prostate cancer cell, an ovarian cancer cell, or a breastcancer cell.

The present invention provides a method for treating an Mnk dependentcondition in a mammal in need thereof, comprising administering to themammal (i) a therapeutically effective amount of at least one compoundaccording to the present application or a stereoisomer, tautomer, orsolvate thereof, or (ii) a pharmaceutical composition the a compound ofthe present application.

In an embodiment, the condition treated by the inventive method iscolorectal cancer, gastric cancer, thyroid cancer, lung cancer,leukemia, B-cell lymphoma, T-cell lymphoma, hairy cell lymphoma,Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma,pancreatic cancer, melanoma, multiple melanoma, brain cancer, CNScancer, renal cancer, prostate cancer, ovarian cancer or breast cancer.In another embodiment, the mammal of the inventive method is a human.

The above embodiments and other aspects of the invention are readilyapparent in the detailed description that follows. To this end, variousreferences are set forth herein which describe in more detail certainbackground information, procedures, compounds and/or compositions, andare each hereby incorporated by reference in their entirety.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 shows the XRPD pattern of Form A of6′-((6-aminopyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione.

FIG. 2 shows the XRPD pattern of Form B of6′-((6-aminopyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione.

FIG. 3 shows the XRPD pattern of Form C of6′-((6-aminopyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione.

FIG. 4 shows the XRPD pattern of Form D of6′-((6-aminopyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione.

DETAILED DESCRIPTION

In the following description, certain specific details are set forth inorder to provide a thorough understanding of various embodiments of theinvention. However, one skilled in the art will understand that theinvention may be practiced without these details. Unless the contextrequires otherwise, throughout the present specification and claims, theword “comprise” and variations thereof, such as, “comprises” and“comprising” are to be construed in an open, inclusive sense (i.e., as“including, but not limited to”).

Reference throughout this specification to “one embodiment” or “anembodiment” means that a particular feature, structure or characteristicdescribed in connection with the embodiment is included in at least oneembodiment of the present invention. Thus, the appearances of thephrases “in one embodiment” or “in an embodiment” in various placesthroughout this specification are not necessarily all referring to thesame embodiment. Furthermore, the particular features, structures, orcharacteristics may be combined in any suitable manner in one or moreembodiments.

Definitions

As used herein, and unless noted to the contrary, the following termsand phrases have the meaning noted below.

The compound of the invention can exist in various isomeric forms, aswell as in one or more tautomeric forms, including both single tautomersand mixtures of tautomers. The term “isomer” is intended to encompassall isomeric forms of a compound of this invention, including tautomericforms of the compound.

Some compounds described here can have asymmetric centers and thereforeexist in different enantiomeric and diastereomeric forms. A compound ofthe invention can be in the form of an optical isomer or a diastereomer.Accordingly, the invention encompasses compounds of the invention andtheir uses as described herein in the form of their optical isomers,diastereoisomers and mixtures thereof, including a racemic mixture.Optical isomers of the compounds of the invention can be obtained byknown techniques such as asymmetric synthesis, chiral chromatography, orvia chemical separation of stereoisomers through the employment ofoptically active resolving agents.

Unless otherwise indicated, “stereoisomer” means one stereoisomer of acompound that is substantially free of other stereoisomers of thatcompound. Thus, a stereomerically pure compound having one chiral centerwill be substantially free of the opposite enantiomer of the compound. Astereomerically pure compound having two chiral centers will besubstantially free of other diastereomers of the compound. A typicalstereomerically pure compound comprises greater than about 80% by weightof one stereoisomer of the compound and less than about 20% by weight ofother stereoisomers of the compound, for example greater than about 90%by weight of one stereoisomer of the compound and less than about 10% byweight of the other stereoisomers of the compound, or greater than about95% by weight of one stereoisomer of the compound and less than about 5%by weight of the other stereoisomers of the compound, or greater thanabout 97% by weight of one stereoisomer of the compound and less thanabout 3% by weight of the other stereoisomers of the compound.

If there is a discrepancy between a depicted structure and a name givento that structure, then the depicted structure controls. Additionally,if the stereochemistry of a structure or a portion of a structure is notindicated with, for example, bold or dashed lines, the structure orportion of the structure is to be interpreted as encompassing allstereoisomers of it. In some cases, however, where more than one chiralcenter exists, the structures and names may be represented as singleenantiomers to help describe the relative stereochemistry. Those skilledin the art of organic synthesis will know if the compounds are preparedas single enantiomers from the methods used to prepare them.

The terms “treat,” “treating” and “treatment” refer to the ameliorationor eradication of a disease or symptoms associated with a disease. Incertain embodiments, such terms refer to minimizing the spread orworsening of the disease resulting from the administration of one ormore prophylactic or therapeutic agents to a patient with such adisease. In the context of the present invention the terms “treat,”“treating” and “treatment” also refer to:

(i) preventing the disease or condition from occurring in a mammal, inparticular, when such mammal is predisposed to the condition but has notyet been diagnosed as having it;

(ii) inhibiting the disease or condition, i.e., arresting itsdevelopment;

(iii) relieving the disease or condition, i.e., causing regression ofthe disease or condition; or

(iv) relieving the symptoms resulting from the disease or condition,i.e., relieving pain without addressing the underlying disease orcondition. As used herein, the terms “disease” and “condition” may beused interchangeably or may be different in that the particular maladyor condition may not have a known causative agent (or that the etiologyhas not yet been worked out) and it is therefore not yet recognized as adisease but only as an undesirable condition or syndrome, wherein a moreor less specific set of symptoms have been identified by clinicians.

The terms “modulate,” “modulation” and the like refer to the ability ofa compound to increase or decrease the function, or activity of, forexample, MAP kinase interacting kinase (Mnk). “Modulation,” in itsvarious forms, is intended to encompass inhibition, antagonism, partialantagonism, activation, agonism and/or partial agonism of the activityassociated with Mnk. Mnk inhibitors are compounds that bind to,partially or totally block stimulation, decrease, prevent, delayactivation, inactivate, desensitize, or down regulate signaltransduction. The ability of a compound to modulate Mnk activity can bedemonstrated in an enzymatic assay or a cell-based assay.

A “patient” or “subject” includes an animal, such as a human, cow,horse, sheep, lamb, pig, chicken, turkey, quail, cat, dog, mouse, rat,rabbit or guinea pig. The animal can be a mammal such as a non-primateand a primate (e.g., monkey and human). In one embodiment, a patient isa human, such as a human infant, child, adolescent or adult.

The term “prodrug” refers to a precursor of a drug, a compound whichupon administration to a patient, must undergo chemical conversion bymetabolic processes before becoming an active pharmacological agent.Exemplary prodrugs of compounds of the present application are esters,acetamides, and amides.

The inventive compounds may be isotopically-labelled by having one ormore atoms replaced by an atom having a different atomic mass or massnumber. Examples of isotopes that can be incorporated include isotopesof hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine,or iodine. Illustrative of such isotopes are ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N,¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I,respectively. These radiolabelled compounds can be used to measure thebiodistribution, tissue concentration and the kinetics of transport andexcretion from biological tissues including a subject to which such alabelled compound is administered. Labeled compounds are also used todetermine therapeutic effectiveness, the site or mode of action, and thebinding affinity of a candidate therapeutic to a pharmacologicallyimportant target. Certain radioactive-labelled compounds are useful indrug and/or tissue distribution studies. The radioactive isotopestritium, i.e., ³H and carbon-14, i.e., ¹⁴C, are particularly useful forthis purpose in view of their ease of incorporation and means ofdetection.

Substitution with heavier isotopes such as deuterium, i.e., ²H, affordscertain therapeutic advantages resulting from the greater metabolicstability, for example, increased in vivo half-life of compoundscontaining deuterium. Substitution of hydrogen with deuterium may reducedose required for therapeutic effect, and hence may be preferred in adiscovery or clinical setting.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, provides labeled analogs of the inventive compounds that are usefulin Positron Emission Tomography (PET) studies, e.g., for examiningsubstrate receptor occupancy. Isotopically-labeled compounds accordingto the present application can generally be prepared by conventionaltechniques known to those skilled in the art or by processes analogousto those described in the Example section as set out below using anappropriate isotopic-labeling reagent.

Embodiments of the invention disclosed herein are also meant toencompass the in vivo metabolic products of compounds of the presentapplication. Such products may result from, for example, the oxidation,reduction, hydrolysis, amidation, esterification, and like processesprimarily due to enzymatic activity upon administration of a compound ofthe invention. Accordingly, the invention includes compounds that areproduced as by-products of enzymatic or non-enzymatic activity on aninventive compound following the administration of such a compound to amammal for a period of time sufficient to yield a metabolic product.Metabolic products, particularly pharmaceutically active metabolites,are typically identified by administering a radiolabelled compound ofthe invention in a detectable dose to a subject, such as rat, mouse,guinea pig, monkey, or human, for a sufficient period of time duringwhich metabolism occurs, and isolating the metabolic products fromurine, blood or other biological samples that are obtained from thesubject receiving the radiolabelled compound.

Often crystallizations produce a solvate of the compound of theinvention. As used herein, the term “solvate” refers to an aggregatethat comprises one or more molecules of a compound of the invention withone or more molecules of solvent. The solvent may be water, in whichcase the solvate may be a hydrate. Alternatively, the solvent may be anorganic solvent. Thus, the compounds of the present invention may existas a hydrate, including a monohydrate, dihydrate, hemihydrate,sesquihydrate, trihydrate, tetrahydrate and the like, as well as thecorresponding solvated forms. The compound of the invention may be truesolvates, while in other cases, the compound of the invention may merelyretain adventitious water or be a mixture of water plus someadventitious solvent.

Compounds of the invention, or their pharmaceutically acceptable saltsmay contain one or more asymmetric centers and may thus give rise toenantiomers, diastereomers, and other stereoisomeric forms that may bedefined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)- for amino acids. The present invention is meant to includeall such possible isomers, as well as their racemic and optically pureforms. Optically active (+) and (−), (R)- and (S)-, or (D)- and(L)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, for example, chromatography andfractional crystallization. Conventional techniques for thepreparation/isolation of individual enantiomers include chiral synthesisfrom a suitable optically pure precursor or resolution of the racemate(or the racemate of a salt or derivative) using, for example, chiralhigh pressure liquid chromatography (HPLC). When the compounds describedherein contain olefinic double bonds or other centers of geometricasymmetry, and unless specified otherwise, it is intended that thecompounds include both E and Z geometric isomers. Likewise, alltautomeric forms are also intended to be included.

The term “tautomer” refers to a proton shift from one atom of a moleculeto another atom of the same molecule.

The inventive compounds are synthesized using conventional syntheticmethods, and more specifically using the general methods noted below.Specific synthetic protocols for compounds in accordance with thepresent invention are described in the Examples.

Pharmaceutical Formulations

In one embodiment, compounds of the present application are formulatedas pharmaceutically acceptable compositions that contain the compound inan amount effective to treat a particular disease or condition ofinterest upon administration of the pharmaceutical composition to amammal. Pharmaceutical compositions in accordance with the presentinvention can comprise a compound in combination with a pharmaceuticallyacceptable carrier, diluent or excipient.

In this regard, a “pharmaceutically acceptable carrier, diluent orexcipient” includes without limitation any adjuvant, carrier, excipient,glidant, sweetening agent, diluent, preservative, dye/colorant, flavorenhancer, surfactant, wetting agent, dispersing agent, suspending agent,stabilizer, isotonic agent, solvent, or emulsifier which has beenapproved by the United States Food and Drug Administration as beingacceptable for use in humans or domestic animals.

Further, a “mammal” includes humans and both domestic animals such aslaboratory animals and household pets (e.g., cats, dogs, swine, cattle,sheep, goats, horses, rabbits), and non-domestic animals such aswildlife and the like.

The pharmaceutical compositions of the invention can be prepared bycombining a compound of the invention with an appropriatepharmaceutically acceptable carrier, diluent or excipient, and may beformulated into preparations in solid, semi-solid, liquid or gaseousforms, such as tablets, capsules, powders, granules, ointments,solutions, suppositories, injections, inhalants, gels, microspheres, andaerosols. Typical routes of administering such pharmaceuticalcompositions include, without limitation, oral, topical, transdermal,inhalation, parenteral, sublingual, buccal, rectal, vaginal, andintranasal. The term parenteral as used herein includes subcutaneousinjections, intravenous, intramuscular, intrasternal injection orinfusion techniques. Pharmaceutical compositions of the invention areformulated so as to allow the active ingredients contained therein to bebioavailable upon administration of the composition to a patient.Compositions that will be administered to a subject or patient take theform of one or more dosage units, where for example, a tablet may be asingle dosage unit, and a container of a compound of the invention inaerosol form may hold a plurality of dosage units. Actual methods ofpreparing such dosage forms are known, or will be apparent, to thoseskilled in this art; for example, see Remington: The Science andPractice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy andScience, 2000). The composition to be administered will, in any event,contain a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof, for treatmentof a disease or condition of interest in accordance with the teachingsof this invention.

A pharmaceutical composition of the invention may be in the form of asolid or liquid. In one aspect, the carrier(s) are particulate, so thatthe compositions are, for example, in tablet or powder form. Thecarrier(s) may be liquid, with the compositions being, for example, anoral syrup, injectable liquid or an aerosol, which is useful in, forexample, inhalatory administration. When intended for oraladministration, the pharmaceutical composition is preferably in eithersolid or liquid form, where semi-solid, semi-liquid, suspension and gelforms are included within the forms considered herein as either solid orliquid.

As a solid composition for oral administration the pharmaceuticalcomposition may be formulated into a powder, granule, compressed tablet,pill, capsule, chewing gum, wafer or the like form. Such a solidcomposition will typically contain one or more inert diluents or ediblecarriers. In addition, one or more of the following may be present:binders such as carboxymethylcellulose, ethyl cellulose,microcrystalline cellulose, gum tragacanth or gelatin; excipients suchas starch, lactose or dextrins, disintegrating agents such as alginicacid, sodium alginate, Primogel, corn starch and the like; lubricantssuch as magnesium stearate or Sterotex; glidants such as colloidalsilicon dioxide; sweetening agents such as sucrose or saccharin; aflavoring agent such as peppermint, methyl salicylate or orangeflavoring; and a coloring agent.

When the pharmaceutical composition is in the form of a capsule, forexample, a gelatin capsule, it may contain, in addition to materials ofthe above type, a liquid carrier such as polyethylene glycol or oil.

The pharmaceutical composition may be in the form of a liquid, forexample, an elixir, syrup, solution, emulsion or suspension. The liquidmay be for oral administration or for delivery by injection, as twoexamples. When intended for oral administration, preferred compositioncontain, in addition to the present compounds, one or more of asweetening agent, preservatives, dye/colorant and flavor enhancer. In acomposition intended to be administered by injection, one or more of asurfactant, preservative, wetting agent, dispersing agent, suspendingagent, buffer, stabilizer and isotonic agent may be included.

The liquid pharmaceutical compositions of the invention, whether they besolutions, suspensions or other like form, may include one or more ofthe following adjuvants: sterile diluents such as water for injection,saline solution, preferably physiological saline, Ringer's solution,isotonic sodium chloride, fixed oils such as synthetic mono ordiglycerides which may serve as the solvent or suspending medium,polyethylene glycols, glycerin, propylene glycol or other solvents;antibacterial agents such as benzyl alcohol or methyl paraben;antioxidants such as ascorbic acid or sodium bisulfite; chelating agentssuch as ethylenediaminetetraacetic acid; buffers such as acetates,citrates or phosphates and agents for the adjustment of tonicity such assodium chloride or dextrose. The parenteral preparation can be enclosedin ampoules, disposable syringes or multiple dose vials made of glass orplastic. Physiological saline is a preferred adjuvant. An injectablepharmaceutical composition is preferably sterile.

A liquid pharmaceutical composition of the invention intended for eitherparenteral or oral administration should contain an amount of a compoundof the invention such that a suitable dosage will be obtained.

The pharmaceutical composition of the invention may be intended fortopical administration, in which case the carrier may suitably comprisea solution, emulsion, ointment or gel base. The base, for example, maycomprise one or more of the following: petrolatum, lanolin, polyethyleneglycols, bee wax, mineral oil, diluents such as water and alcohol, andemulsifiers and stabilizers. Thickening agents may be present in apharmaceutical composition for topical administration. If intended fortransdermal administration, the composition may include a transdermalpatch or iontophoresis device.

The pharmaceutical composition of the invention may be intended forrectal administration, in the form, for example, of a suppository, whichwill melt in the rectum and release the drug. The composition for rectaladministration may contain an oleaginous base as a suitablenonirritating excipient. Such bases include, without limitation,lanolin, cocoa butter and polyethylene glycol.

The pharmaceutical composition of the invention may include variousmaterials, which modify the physical form of a solid or liquid dosageunit. For example, the composition may include materials that form acoating shell around the active ingredients. The materials that form thecoating shell are typically inert, and may be selected from, forexample, sugar, shellac, and other enteric coating agents.Alternatively, the active ingredients may be encased in a gelatincapsule.

The pharmaceutical composition of the invention in solid or liquid formmay include an agent that binds to the compound of the invention andthereby assists in the delivery of the compound. Suitable agents thatmay act in this capacity include a monoclonal or polyclonal antibody, aprotein or a liposome.

The pharmaceutical composition of the invention may consist of dosageunits that can be administered as an aerosol. The term aerosol is usedto denote a variety of systems ranging from those of colloidal nature tosystems consisting of pressurized packages. Delivery may be by aliquefied or compressed gas or by a suitable pump system that dispensesthe active ingredients. Aerosols of compounds of the invention may bedelivered in single phase, bi-phasic, or tri-phasic systems in order todeliver the active ingredient(s). Delivery of the aerosol includes thenecessary container, activators, valves, subcontainers, and the like,which together may form a kit. One skilled in the art, without undueexperimentation may determine preferred aerosols.

The pharmaceutical compositions of the invention may be prepared by anymethodology well known in the pharmaceutical art. For example, apharmaceutical composition intended to be administered by injection canbe prepared by combining a compound of the invention with sterile,distilled water so as to form a solution. A surfactant may be added tofacilitate the formation of a homogeneous solution or suspension.Surfactants are compounds that non-covalently interact with the compoundof the invention so as to facilitate dissolution or homogeneoussuspension of the compound in the aqueous delivery system.

In certain embodiments a pharmaceutical composition comprising acompound of the present application is administered to a mammal in anamount sufficient to inhibit Mnk activity upon administration, andpreferably with acceptable toxicity to the same. Mnk activity of thecrystalline form of the compounds of the present application can bedetermined by one skilled in the art, for example, as described in theExamples below. Appropriate concentrations and dosages can be readilydetermined by one skilled in the art.

In a further aspect of the invention the inventive compounds orpharmaceutically acceptable formulations of the inventive compounds areprovided as inhibitors of Mnk activity. Such inhibition is achieved bycontacting a cell expressing Mnk with a compound or a pharmaceuticallyacceptable formulation, to lower or inhibit Mnk activity, to providetherapeutic efficacy for a Mnk dependent condition in a mammal in needthereof.

Therapeutically effective dosages of a compound according to the presentapplication or a pharmaceutical composition of the present applicationwill generally range from about 1 to 2000 mg/day, from about 10 to about1000 mg/day, from about 10 to about 500 mg/day, from about 10 to about250 mg/day, from about 10 to about 100 mg/day, or from about 10 to about50 mg/day. The therapeutically effective dosages may be administered inone or multiple doses. It will be appreciated, however, that specificdoses of the compounds of the invention for any particular patient willdepend on a variety of factors such as age, sex, body weight, generalhealth condition, diet, individual response of the patient to betreated, time of administration, severity of the disease to be treated,the activity of particular compound applied, dosage form, mode ofapplication and concomitant medication. The therapeutically effectiveamount for a given situation will readily be determined by routineexperimentation and is within the skills and judgment of the ordinaryclinician or physician. In any case, the compound or composition will beadministered at dosages in a manner which allows a therapeuticallyeffective amount to be delivered based upon patient's unique condition.

A dosage form as presently described can also preferably include adisintegrant, which functions to cause the dosage form to expand andbreak up during use, e.g., at conditions of a human stomach, to allowactive pharmaceutical ingredient of the dosage form to be released in amanner to achieve an immediate release profile. Disintegrants areingredients of pharmaceutical dosage forms, with various examples beingknown and commercially available. Examples of disintegrants includecompositions of or containing citric acid, sodium bicarbonate, or anycombination of two or more of the foregoing, and other pharmaceuticallyacceptable materials formed into particles having a particle size,density, etc., to allow processing of the disintegrant into a usefulimmediate release dosage form.

The disintegrant can be present in an immediate release dosage form atany location that allows the disintegrant to function as desired, toexpand within the intact dosage form, upon ingestion, to cause theingested dosage form to break apart and allow for desired immediaterelease of active pharmaceutical ingredient from the dosage form, in astomach. One useful location for a disintegrant can be as a component ofan excipient used to contain core-shell particles that contain activepharmaceutical ingredient, as described herein, in a dosage form such asa compressed tablet or capsule.

When included as an excipient of a dosage form, disintegrant may bepresent in an amount useful to achieve immediate release of an API of adosage form. Examples of useful amounts of disintegrant in an immediaterelease dosage form as described herein may be in a range from 0.5 to 50weight percent disintegrant based on a total weight of the dosage form,e.g., from 1 to 30 weight percent disintegrant based on total weight ofthe dosage form. The amount of disintegrant in a matrix of a dosage formcan be consistent with these amounts, e.g., disintegrant can be includedin a matrix (e.g., total of a dosage form that is other than the coatedparticles or API) of a dosage form in an amount in a range from 0.5 to50 weight percent disintegrant based on a total weight of the matrix,e.g., from 1 to 30 weight percent disintegrant based on total weightmatrix.

A dosage form as described can also include any of various known andconventional pharmaceutical excipients that may be useful to achievedesired processing and performance properties of an immediate releasedosage form. These excipients include fillers, binders, lubricants,glidants, etc., and can be included in core-shell particles or in amatrix (e.g., compressed matrix) of a tablet or capsule. A more detaileddescription of pharmaceutical excipients that may also be included inthe tablets of the present invention can be found in The Handbook ofPharmaceutical Excipients, 5th ed. (2006).

Examples of fillers that may be useful in an immediate release dosageform as described include lactose, starch, dextrose, sucrose, fructose,maltose, mannitol, sorbitol, kaolin, microcrystalline cellulose,powdered cellulose, calcium sulfate, calcium phosphate, dicalciumphosphate, lactitol or any combination of the foregoing.

A filler may be present in any portion of a dosage form as described,including a core-shell particle; the filler may be present in a core, ina layer containing an active pharmaceutical ingredient that is disposedon the core, in a solvent resistant film, in the matrix, or in two ormore of these portions of the dosage form. The filler may be present atany one or more of these portions of a dosage form in an amount toprovide desired processing or functional properties of a portion of thedosage form and of the entire dosage form. The amount of total filler ina dosage form can also be as desired to provide desired functionality,including an immediate release profile, for example in an amount in arange from 0 to 80 weight percent filler based upon the total weight ofthe dosage form, e.g. from 5 to 50 percent filler based on total weightdosage form.

Examples of lubricants include inorganic materials such as talc (ahydrated magnesium silicate; polymers, such as, PEG 4000; fatty acids,such as stearic acid; fatty acid esters, such as glyceride esters (e.g.,glyceryl monostearate, glyceryl tribehenate, and glyceryl dibehenate);sugar esters (e.g., sorbitan monostearate and sucrose monopalmitate);glyceryl dibehenate; and metal salts of fatty acids (e.g., sodium laurylsulfate, magnesium stearate, calcium stearate, and zinc stearate).Lubricant may be included in an immediate release dosage form, in anyuseful amount, such as an amount in a range from 0.1 to 10 weightpercent lubricant based on a total weight of a dosage form, e.g., from0.5 to 7 weight percent lubricant based on total weight dosage form.

Examples of glidants include colloidal silicon dioxide, untreated fumedsilica (AEROSOL 200®), and crystalline or fused quartz. Glidant may beincluded in an immediate release dosage form as described, in any usefulamount.

Therapeutic Use

The compounds of the invention, or their pharmaceutically acceptablesalts, are administered in a therapeutically effective amount, whichwill vary depending upon a variety of factors including the activity ofthe specific compound employed; the metabolic stability and length ofaction of the compound; the age, body weight, general health, sex, anddiet of the patient; the mode and time of administration; the rate ofexcretion; the drug combination; the severity of the particular disorderor condition; and the subject undergoing therapy.

“Effective amount” or “therapeutically effective amount” refers to thatamount of a compound of the invention which, when administered to amammal, preferably a human, is sufficient to effect treatment, asdefined below, of a Mnk related condition or disease in the mammal,preferably a human. The amount of a compound of the invention whichconstitutes a “therapeutically effective amount” will vary depending onthe compound, the condition and its severity, the manner ofadministration, and the age of the mammal to be treated, but can bedetermined routinely by one of ordinary skill in the art having regardto his own knowledge and to this disclosure.

Compounds of the invention, or pharmaceutically acceptable salt thereof,may also be administered simultaneously with, prior to, or afteradministration of one or more other therapeutic agents. Such combinationtherapy includes administration of a single pharmaceutical dosageformulation which contains a compound of the invention and one or moreadditional active agents, as well as administration of the compound ofthe invention and each active agent in its own separate pharmaceuticaldosage formulation. For example, a compound of the invention and theother active agent can be administered to the patient together in asingle oral dosage composition such as a tablet or capsule, or eachagent administered in separate oral dosage formulations. Where separatedosage formulations are used, the compounds of the invention and one ormore additional active agents can be administered at essentially thesame time, i.e., concurrently, or at separately staggered times, i.e.,sequentially; combination therapy is understood to include all theseregimens.

In certain embodiments the disclosed compounds are useful for inhibitingthe activity of Mnk and/or can be useful in analyzing Mnk signalingactivity in model systems and/or for preventing, treating, orameliorating a symptom associated with a disease, disorder, orpathological condition involving Mnk, preferably one afflicting humans.A compound which inhibits the activity of Mnk will be useful inpreventing, treating, ameliorating, or reducing the symptoms orprogression of diseases of uncontrolled cell growth, proliferationand/or survival, inappropriate cellular immune responses, orinappropriate cellular inflammatory responses or diseases which areaccompanied with uncontrolled cell growth, proliferation and/orsurvival, inappropriate cellular immune responses, or inappropriatecellular inflammatory responses, particularly in which the uncontrolledcell growth, proliferation and/or survival, inappropriate cellularimmune responses, or inappropriate cellular inflammatory responses ismediated by Mnk, such as, for example, haematological tumors, solidtumors, and/or metastases thereof, including leukaemias andmyelodysplastic syndrome, Waldenstrom macroglobulinemia, and malignantlymphomas, for example, B-cell lymphoma, T-cell lymphoma, hairy celllymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, and Burkitt'slymphoma, head and neck tumors including brain tumors and brainmetastases, tumors of the thorax including non-small cell and small celllung tumors, gastrointestinal tumors, endocrine tumors, mammary andother gynecological tumors, urological tumors including renal, bladderand prostate tumors, skin tumors, and sarcomas, and/or metastasesthereof.

Furthermore, the inventive compounds and their pharmaceuticalcompositions are candidate therapeutics for the prophylaxis and/ortherapy of cytokine related diseases, such as inflammatory diseases,allergies, or other conditions associated with proinflammatorycytokines. Exemplary inflammatory diseases include without limitation,chronic or acute inflammation, inflammation of the joints such aschronic inflammatory arthritis, rheumatoid arthritis, psoriaticarthritis, osteoarthritis, juvenile rheumatoid arthritis, Reiter'ssyndrome, rheumatoid traumatic arthritis, rubella arthritis, acutesynovitis and gouty arthritis; inflammatory skin diseases such assunburn, psoriasis, erythrodermic psoriasis, pustular psoriasis, eczema,dermatitis, acute or chronic graft formation, atopic dermatitis, contactdermatitis, urticaria and scleroderma; inflammation of thegastrointestinal tract such as inflammatory bowel disease, Crohn'sdisease and related conditions, ulcerative colitis, colitis, anddiverticulitis; nephritis, urethritis, salpingitis, oophoritis,endomyometritis, spondylitis, systemic lupus erythematosus and relateddisorders, multiple sclerosis, asthma, meningitis, myelitis,encephalomyelitis, encephalitis, phlebitis, thrombophlebitis,respiratory diseases such as asthma, bronchitis, chronic obstructivepulmonary disease (COPD), inflammatory lung disease and adultrespiratory distress syndrome, and allergic rhinitis; endocarditis,osteomyelitis, rheumatic fever, rheumatic pericarditis, rheumaticendocarditis, rheumatic myocarditis, rheumatic mitral valve disease,rheumatic aortic valve disease, prostatitis, prostatocystitis,spondoarthropathies ankylosing spondylitis, synovitis, tenosynovotis,myositis, pharyngitis, polymyalgia rheumatica, shoulder tendonitis orbursitis, gout, pseudo gout, vasculitides, inflammatory diseases of thethyroid selected from granulomatous thyroiditis, lymphocyticthyroiditis, invasive fibrous thyroiditis, acute thyroiditis;Hashimoto's thyroiditis, Kawasaki's disease, Raynaud's phenomenon,Sjogren's syndrome, neuroinflammatory disease, sepsis, conjunctivitis,keratitis, iridocyclitis, optic neuritis, otitis, lymphoadenitis,nasopaharingitis, sinusitis, pharyngitis, tonsillitis, laryngitis,epiglottitis, bronchitis, pneumonitis, stomatitis, gingivitis,oesophagitis, gastritis, peritonitis, hepatitis, cholelithiasis,cholecystitis, glomerulonephritis, goodpasture's disease, crescenticglomerulonephritis, pancreatitis, endomyometritis, myometritis,metritis, cervicitis, endocervicitis, exocervicitis, parametritis,tuberculosis, vaginitis, vulvitis, silicosis, sarcoidosis,pneumoconiosis, pyresis, inflammatory polyarthropathies, psoriatricarthropathies, intestinal fibrosis, bronchiectasis and enteropathicarthropathies.

Accordingly, certain embodiments are directed to a method for treating aMnk dependent condition in a mammal in need thereof, the methodcomprising administering an effective amount of a pharmaceuticalcomposition as described above (i.e., a pharmaceutical compositioncomprising any one or more compounds of the present application to amammal.

As described above deregulation of protein synthesis is a common eventin human cancers. A key regulator of translational control is eIF4Ewhose activity is a key determinant of tumorigenicity. Becauseactivation of eIF4E involves phosphorylation of a key serine (Ser209)specifically by MAP kinase interacting kinases (Mnk), inhibitors of Mnkare suitable candidate therapeutics for treating cell proliferativedisorders such as cancer. A wide variety of cancers, including solidtumors, lymphomas and leukemias, are amenable to the compositions andmethods disclosed herein. Types of cancer that may be treated include,but are not limited to: adenocarcinoma of the breast, prostate andcolon; all forms of bronchogenic carcinoma of the lung; myeloid;melanoma; hepatoma; neuroblastoma; papilloma; apudoma; choristoma;branchioma; malignant carcinoid syndrome; carcinoid heart disease; andcarcinoma (e.g., Walker, basal cell, basosquamous, Brown-Pearce, ductal,Ehrlich tumor, Krebs 2, merkel cell, mucinous, non-small cell lung, oatcell, papillary, scirrhous, bronchiolar, bronchogenic, squamous cell,and transitional cell). Additional types of cancers that may be treatedinclude: histiocytic disorders; acute and chronic leukemia, both myeloidand lymphoid/lymphoblastic, including hairy cell leukemia; histiocytosismalignant; Hodgkin's disease; immunoproliferative small; Hodgkin'slymphoma; B-cell and T-cell non-Hodgkin's lymphoma, including diffuselarge B-cell and Burkitt's lymphoma; plasmacytoma;reticuloendotheliosis; melanoma; multiple myeloma; chondroblastoma;chondroma; chondrosarcoma; fibroma; fibrosarcoma; myelofibrosis; giantcell tumors; histiocytoma; lipoma; liposarcoma; mesothelioma; myxoma;myxosarcoma; osteoma; osteosarcoma; chordoma; craniopharyngioma;dysgerminoma; hamartoma; mesenchymoma; mesonephroma; myosarcoma;ameloblastoma; cementoma; odontoma; teratoma; thymoma; trophoblastictumor.

Other cancers that can be treated using the inventive compounds includewithout limitation adenoma; cholangioma; cholesteatoma; cyclindroma;cystadenocarcinoma; cystadenoma; granulosa cell tumor; gynandroblastoma;hepatoma; hidradenoma; islet cell tumor; Leydig cell tumor; papilloma;sertoli cell tumor; theca cell tumor; leimyoma; leiomyosarcoma;myoblastoma; myomma; myosarcoma; rhabdomyoma; rhabdomyosarcoma;ependymoma; ganglioneuroma; glioma; medulloblastoma; meningioma;neurilemmoma; neuroblastoma; neuroepithelioma; neurofibroma; neuroma;paraganglioma; paraganglioma nonchromaffin.

In one embodiment the inventive compounds are candidate therapeuticagents for the treatment of cancers such as angiokeratoma; angiolymphoidhyperplasia with eosinophilia; angioma sclerosing; angiomatosis;glomangioma; hemangioendothelioma; hemangioma; hemangiopericytoma;hemangiosarcoma; lymphangioma; lymphangiomyoma; lymphangiosarcoma;pinealoma; carcinosarcoma; chondrosarcoma; cystosarcoma phyllodes;fibrosarcoma; hemangiosarcoma; leiomyosarcoma; leukosarcoma;liposarcoma; lymphangiosarcoma; myosarcoma; myxosarcoma; ovariancarcinoma; rhabdomyosarcoma; sarcoma; neoplasms; nerofibromatosis; andcervical dysplasia.

In a particular embodiment the present disclosure provides methods fortreating colon cancer, colorectal cancer, gastric cancer, thyroidcancer, lung cancer, leukemia, pancreatic cancer, melanoma, multiplemelanoma, brain cancer, primary and secondary CNS cancer, includingmalignant glioma and glioblastoma, renal cancer, prostate cancer,including castration-resistant prostate cancer, ovarian cancer, orbreast cancer, including triple negative, HER2 positive, and hormonereceptor positive breast cancers. According to such a method, atherapeutically effective amount of at least one compound of the presentapplication or a stereoisomer, tautomer, or solvate thereof can beadministered to a subject who has been diagnosed with a cellproliferative disease, such as a cancer. Alternatively, a pharmaceuticalcomposition comprising at least one compound of the present applicationor a stereoisomer, tautomer, or solvate thereof can be administered to asubject who has been diagnosed with cancer.

In certain embodiments the compounds in accordance with the inventionare administered to a subject with cancer in conjunction with otherconventional cancer therapies such as radiation treatment or surgery.Radiation therapy is well known in the art and includes X-ray therapies,such as gamma-irradiation, and radiopharmaceutical therapies.

In certain embodiments the inventive Mnk inhibitor compounds are usedwith at least one anti-cancer agent. Anti-cancer agents includechemotherapeutic drugs. A chemotherapeutic agent includes, but is notlimited to, an inhibitor of chromatin function, a topoisomeraseinhibitor, a microtubule inhibiting drug, a DNA damaging agent, anantimetabolite (such as folate antagonists, pyrimidine analogs, purineanalogs, and sugar-modified analogs), a DNA synthesis inhibitor, a DNAinteractive agent (such as an intercalating agent), and a DNA repairinhibitor.

Illustrative chemotherapeutic agents include, without limitation, thefollowing groups: anti-metabolites/anti-cancer agents, such aspyrimidine analogs (5-fluorouracil, floxuridine, capecitabine,gemcitabine and cytarabine) and purine analogs, folate antagonists andrelated inhibitors (mercaptopurine, thioguanine, pentostatin and2-chlorodeoxyadenosine (cladribine)); antiproliferative/antimitoticagents including natural products such as vinca alkaloids (vinblastine,vincristine, and vinorelbine), microtubule disruptors such as taxane(paclitaxel, docetaxel), vincristin, vinblastin, nocodazole, epothilonesand navelbine, epidipodophyllotoxins (etoposide, teniposide), DNAdamaging agents (actinomycin, amsacrine, anthracyclines, bleomycin,busulfan, camptothecin, carboplatin, chlorambucil, cisplatin,cyclophosphamide, Cytoxan, dactinomycin, daunorubicin, doxorubicin,epirubicin, hexamethylmelamineoxaliplatin, iphosphamide, melphalan,merchlorehtamine, mitomycin, mitoxantrone, nitrosourea, plicamycin,procarbazine, taxol, taxotere, temozolamide, teniposide,triethylenethiophosphoramide and etoposide (VP 16)); antibiotics such asdactinomycin (actinomycin D), daunorubicin, doxorubicin (adriamycin),idarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin(mithramycin) and mitomycin; enzymes (L-asparaginase which systemicallymetabolizes L-asparagine and deprives cells which do not have thecapacity to synthesize their own asparagine); antiplatelet agents;antiproliferative/antimitotic alkylating agents such as nitrogenmustards (mechlorethamine, cyclophosphamide and analogs, melphalan,chlorambucil), ethylenimines and methylmelamines (hexamethylmelamine andthiotepa), alkyl sulfonates-busulfan, nitrosoureas (carmustine (BCNU)and analogs, streptozocin), trazenes-dacarbazinine (DTIC);antiproliferative/antimitotic antimetabolites such as folic acid analogs(methotrexate); platinum coordination complexes (cisplatin,carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide;hormones, hormone analogs (estrogen, tamoxifen, goserelin, bicalutamide,nilutamide) and aromatase inhibitors (letrozole, anastrozole);anticoagulants (heparin, synthetic heparin salts and other inhibitors ofthrombin); fibrinolytic agents (such as tissue plasminogen activator,streptokinase and urokinase), aspirin, dipyridamole, ticlopidine,clopidogrel, abciximab; antimigratory agents; antisecretory agents(breveldin); immunosuppressives (cyclosporine, tacrolimus (FK-506),sirolimus (rapamycin), azathioprine, mycophenolate mofetil);anti-angiogenic compounds (TNP470, genistein) and growth factorinhibitors (vascular endothelial growth factor (VEGF) inhibitors,fibroblast growth factor (FGF) inhibitors); angiotensin receptorblocker; nitric oxide donors; anti-sense oligonucleotides; antibodies(trastuzumab, rituximab); chimeric antigen receptors; cell cycleinhibitors and differentiation inducers (tretinoin); mTOR inhibitors,topoisomerase inhibitors (doxorubicin (adriamycin), amsacrine,camptothecin, daunorubicin, dactinomycin, eniposide, epirubicin,etoposide, idarubicin, irinotecan (CPT-11) and mitoxantrone, topotecan,irinotecan), corticosteroids (cortisone, dexamethasone, hydrocortisone,methylpednisolone, prednisone, and prenisolone); growth factor signaltransduction kinase inhibitors; mitochondrial dysfunction inducers,toxins such as Cholera toxin, ricin, Pseudomonas exotoxin, Bordetellapertussis adenylate cyclase toxin, or diphtheria toxin, and caspaseactivators; and chromatin disruptors.

In certain embodiments an Mnk inhibitor in accordance with the presentinvention is used simultaneously, in the same formulation or in separateformulations, or sequentially with an additional agent(s) as part of acombination therapy regimen.

Mnk inhibitors according to the present application including theircorresponding solvates and pharmaceutical compositions are alsoeffective as therapeutic agents for treating or preventing cytokinemediated disorders, such as inflammation in a patient, preferably in ahuman. In one embodiment, a compound or composition in accordance withthe invention is particularly useful for treating or preventing adisease selected from chronic or acute inflammation, chronicinflammatory arthritis, rheumatoid arthritis, psoriasis, COPD,inflammatory bowel disease, septic shock, Crohn's disease, ulcerativecolitis, multiple sclerosis and asthma.

The inventive compounds, their corresponding solvates andpharmaceutically acceptable compositions are candidate therapeutics fortreating brain related disorders which include without limitationautism, Fragile X-syndrome, Parkinson's disease and Alzheimer's disease.Treatment is effected by administering to a subject in need of treatmenta compound of the present application, or a pharmaceutically acceptablecomposition thereof.

EXAMPLES

In the synthetic schemes described below, unless otherwise indicated alltemperatures are set forth in degrees Celsius and all parts andpercentages are by weight. Reagents are purchased from commercialsuppliers and are used without further purification unless otherwiseindicated. All solvents are purchased from commercial suppliers and areused as received.

The reactions set forth below are done generally under a positivepressure of nitrogen or argon at an ambient temperature (unlessotherwise stated) in anhydrous solvents, and the reaction vessels arefitted with rubber septa (for flasks) or caps (for vials) for theintroduction of substrates and reagents via syringe. Glassware is ovendried and/or heat dried. The reactions are assayed by TLC and/oranalyzed by LC-MS and terminated as judged by the consumption ofstarting material. Occasionally, reactions are terminated early asdesired products start to decompose.

Analytical thin layer chromatography (TLC) may be performed onglass-plates precoated with silica gel 60 F₂₅₄ 0.25 mm plates (EMDChemicals), and visualized with UV light (254 nm) and/or iodine onsilica gel and/or heating with TLC stains such as ethanolicphosphomolybdic acid, ninhydrin solution, potassium permanganatesolution or ceric sulfate solution.

¹H-NMR spectra may be recorded on a Varian spectrometer operating at 400MHz. NMR spectra are obtained as CDCl₃ solutions (reported in ppm),using chloroform as the reference standard (7.27 ppm for the proton and77.00 ppm for carbon), CD₃OD solutions using 3.4 ppm and 4.8 ppm asreference standards for the protons and 49.3 ppm as a reference standardfor carbon, DMSO-d₆ (2.49 ppm for proton), or internallytetramethylsilane (0.00 ppm) when appropriate. Other NMR solvents areused as needed. When peak multiplicities are reported, the followingabbreviations are used: s (singlet), d (doublet), t (triplet), q(quartet), m (multiplet), br (broadened), bs (broad singlet), dd(doublet of doublets), dt (doublet of triplets). Coupling constants,when given, are reported in Hertz (Hz).

The following examples are provided for purpose of illustration only.

Example 1: Synthetic Scheme for Crystalline Form A of6′-((6-aminopyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(5)

Synthesis of Crystalline Form A of (5).

5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (1) wascombined with cyclohexanone in 1,4-dioxane. Sulfuric acid was added andthe batch temperature is adjusted to 55° C. to 65° C. Typical reactiontime was 1 hour. After completion, the batch temperature was adjusted to10° C. to 30° C. and agitated for approximately 6 hours. The resultingsolids were filtered, washed with water, and then dried under vacuum togive bromide (2) in an approximate yield of 92%.

Bromide (2) was combined with aminopyrimidine (3) with potassiumcarbonate, palladium (II) acetate, and4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) in1,4-dioxane under nitrogen. The batch temperature was adjusted to 90° C.to 100° C. and stirred for approximately 18 hours. After completion, thetemperature was adjusted to room temperature and then water was added.The resulting solid was filtered and then washed with methanol. Thesolids were slurried in methanol at 55° C. to 65° C. with optionalseeding, cooled, filtered, and then dried under vacuum to affordcyclopropylpyrimidine (4) in an approximate yield of 98%.

Cyclopropylpyrimidine (4) was agitated with water, ethanol, andethylenediamine and then treated with potassium hydroxide at 30° C. to40° C. Agitation was continued until reaction was complete by HPLC. Asecond portion of potassium hydroxide was optionally added. Typicalreaction time was 12 hours. The mixture was filtered and the filtratewas treated with hydrochloric acid until the pH was approximately 9 toafford 6-aminopyrimidine (5) as the free base.

6-aminopyrimidine (5) was returned to the reactor and suspended withaqueous ethanol at 35° C. to 45° C., cooled to room temperature,filtered, and then washed with ethanol. The wet cake was dried undervacuum to constant weight to afford Form A of6′-((6-aminopyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(5) in an approximate yield of 79%. See FIG. 1 and Table 1.

Low solubilities of cyclopropylpyrimidine (4) and the free base of6-aminopyrimidine (5) and the hydrochloric salt of (5) precluded the useof common solid-supported palladium scavenging agents (e.g., SILIAMETS®Thiol). The reaction mixture was homogenous after base hydrolysis of thecyclopropylamide (KOH in 1:1:1 THF/ethanol/water), where the use ofethylenediamine was surprisingly found to lower the palladium (II)levels to meet the permissible daily exposure limit based on theclinical dose. While earlier studies employed the use of activatedcarbon, this was unable to reduce the residual palladium levels to meetthe permissible daily exposure limit based on the clinical dose.

A kinetic study identified ethanol as the solvent system for the finalslurry step of the synthesis of Form A to ensure formation of the highlystable crystalline solid. For example, the free base of (5) was slurriedat ambient temperature in various solvent systems, at varioustemperatures, with varying amounts of water. In each solvent condition,solids were isolated for XRPD analysis at 2, 4, 6, 24, and 72 hours.Equilibrium solubilities in these solvents were then calculated and usedto identify ethanol for the final slurry step. The difference in freeenergy between solid phases with the same composition (i.e., polymorphs,hydrates, or solvates) is directly proportional to their relativesolubilities. The most thermodynamically stable polymorph is Form Aunder the conditions examined.

TABLE 1 XRPD peak table for Form A of Compound (5) Relative 2θ intensity(deg) (a.u.) 8.07 27 10.81 44 12.00 7 12.37 5 13.79 3 14.68 26 15.39 416.19 1 16.69 15 17.34 11 18.89 8 20.26 7 21.15 1 21.30 2 21.77 8 22.07100 22.84 2 23.49 2 24.40 1 24.90 1 25.34 3 25.75 1 26.12 2 26.54 427.16 10 27.48 1 28.06 5 28.76 13 29.04 1 29.26 1 29.59 2

Synthesis of Crystalline Form B of (5).

Using the free base of (5) as synthesized above, 6-aminopyrimidine (5)was suspended with a 39:61 (v/v) mixture of isopropanol/chloroform. Thesuspension was dried under a nitrogen gas purge to afford Form B of (5).See FIG. 2 and Table 2.

TABLE 2 XRPD peak table for Form B of Compound (5) Relative 2θ intensity(deg) (a.u) 6.31 6 8.78 100 9.31 15 12.15 10 12.67 3 13.30 3 15.90 616.45 8 17.01 17 17.31 8 17.63 7 17.79 15 18.71 4 18.97 15 19.84 1620.22 11 21.49 22 22.55 11 23.23 8 23.96 12 26.28 10 26.59 5

Synthesis of Crystalline Form C of (5).

Using the free base of (5), 6-aminopyrimidine (5) in a sufficient amountwas combined with ethylenediamine to afford a slurry. The slurry wassealed in a reactor and stirred at room temperature or at 40° C. for 4-5days to afford Form C of Compound (5). Characterization data showed thatForm C is a mono-solvate of ethylenediamine. See FIG. 3 and Table 3.

TABLE 3 XRPD peak table for Form C of Compound (5) Relative 2θ intensity(deg) (a.u) 6.98 45 7.58 83 10.03 54 10.59 18 14.93 46 16.32 61 16.68 819.04 37 19.95 21 20.13 23 20.87 17 21.07 13 21.43 29 22.81 12 24.94 1025.37 13 25.85 100 26.98 52 27.59 12 27.80 18 28.21 8 28.83 6 29.78 8

Synthesis of Crystalline Form D of (5).

6-aminopyrimidine (5) was combined with a 25:75 (v/v) solution ofethanol/hexafluoroisopropanol to afford a concentrated mixture in asmall vial. The vial was uncapped and placed inside a sealed containercontaining ethanol as the anti-solvent. The sealed container was kept atambient conditions until the presence of solids in solution was detectedto provide Form D of (5). Characterization data showed that Form D is ahexafluoroisopropanol solvate. See FIG. 4 and Table 4.

TABLE 4 XRPD peak table for Form D of Compound (5) Relative 2θ intensity(deg) (a.u) 5.61 82 8.53 10 10.62 27 11.24 98 13.20 14 14.07 12 15.48 6116.25 14 16.91 77 17.14 23 17.59 100 18.10 63 18.74 42 19.61 16 19.78 3020.14 98 20.80 15 21.16 20 21.37 13 21.79 65 22.34 11 22.62 19 23.36 924.18 15 24.43 9 25.44 13 26.12 8 26.49 19 27.10 8 27.56 6 27.84 7 28.867 29.43 6

Example 2: Capsule Formulation of Form A

Referring to Table 5, a pharmaceutical composition comprisingcrystalline solids of the present application may includepharmaceutically acceptable carriers, diluents, and/or excipients. In anon-limiting embodiment, the composition comprises Form A of (5), adisintegrant, a filler, a lubricant, and a glidant. It was found thatthe microionization of the free base including excipients provided acapsule formulation with unexpected stability versus the hydrochloricacid salt of (5) as a powder-in-bottle formulation.

TABLE 5 Capsule Formulation of Form A of Compound (5) Quantity ComponentFunction (mg/unit dose) Compound 5 Active Ingredient 100.0 Avicel PH 200Filler 99.7 (microcrystalline cellulose) Citric acid Disintegrant 34.3Sodium bicarbonate Disintegrant 45.0 Sodium lauryl sulfate Lubricant15.0 Aerosol 200 (fumed Glidant 3.0 silica) Magnesium stearate Lubricant3.0

The various embodiments described above can be combined to providefurther embodiments. All of the U.S. patents, U.S. patent applicationpublications, U.S. patent applications, foreign patents, foreign patentapplications and non-patent publications referred to in thisspecification and/or listed in the Application Data Sheet areincorporated herein by reference, in their entirety. Aspects of theembodiments can be modified, if necessary to employ concepts of thevarious patents, applications and publications to provide yet furtherembodiments.

These and other changes can be made to the embodiments in light of theabove-detailed description. In general, in the following claims, theterms used should not be construed to limit the claims to the specificembodiments disclosed in the specification and the claims, but should beconstrued to include all possible embodiments along with the full scopeof equivalents to which such claims are entitled. Accordingly, theclaims are not limited by the disclosure.

1. A crystalline solid of a compound having the structure:

or stereoisomers, tautomers, or solvates thereof.
 2. The crystallinesolid of claim 1, wherein the crystalline solid of the compound has anX-ray powder diffraction pattern with characteristic peaks expressed invalues of degrees 2Θ at about 8.07; about 10.81; about 14.68; and about22.07±0.2.
 3. The crystalline solid of claim 1, wherein the crystallinesolid of the compound has an X-ray powder diffraction pattern withcharacteristic peaks expressed in values of degrees 2Θ at about 8.07;about 10.81; about 14.68; about 16.69; about 17.34; and about 22.07±0.2.4. The crystalline solid of claim 1, wherein the crystalline solid ofthe compound has an X-ray powder diffraction pattern with characteristicpeaks expressed in values of degrees 2Θ at about 8.07; about 10.81;about 12.00; about 12.37; about 13.79; about 14.68; about 15.39; about16.19; about 16.69; about 17.34; about 18.89; about 20.26; about 21.15;about 21.30; about 21.77; about 22.07; about 22.84; about 23.49; about24.40; about 24.90; about 25.34; about 25.75; about 26.12; about 26.54;about 27.16; about 27.48; about 28.06; about 28.76; about 29.04; about29.26; and about 29.59±0.2.
 5. The crystalline solid of claim 1, whereinthe crystalline solid is characterized by an X-ray powder diffractionpattern substantially as shown in FIG.
 1. 6. A pharmaceuticalcomposition comprising (i) a therapeutically effective amount of atleast one crystalline solid according to claim 1 or a stereoisomer,tautomer, or solvate thereof; (ii) in combination with apharmaceutically acceptable carrier, diluent or excipient.
 7. Thepharmaceutical composition of claim 6, wherein the pharmaceuticallyacceptable excipient comprises: (a) a microcrystalline cellulose in theamount of 20.0 to 40.0 w/w % by total weight of composition; (b) citricacid ranging in the amount of 5.0 to 20.0 w/w % by total weight ofcomposition; (c) sodium bicarbonate in the amount of 5.0 to 25.0 w/w %by total weight of composition; (d) sodium lauryl sulfate in the amountof 1.0 to 10.0 w/w % by total weight of composition; (e) fumed silica inthe amount of 0.1 to 5.0 w/w % by total weight of composition; and (f)magnesium stearate in the amount of 0.1 to 5.0 w/w % by total weight ofcomposition.
 8. The pharmaceutical composition of claim 7, wherein thepharmaceutically acceptable excipient comprises: (a) a microcrystallinecellulose in the amount of 25.0 to 35.0 w/w % by total weight ofcomposition; (b) citric acid ranging in the amount of 15.0 to 25.0 w/w %by total weight of composition; (c) sodium bicarbonate in the amount of10.0 to 20.0 w/w % by total weight of composition; (d) sodium laurylsulfate in the amount of 3.0 to 8.0 w/w % by total weight ofcomposition; (e) fumed silica in the amount of 0.1 to 2.0 w/w % by totalweight of composition; and (f) magnesium stearate in the amount of 0.1to 2.0 w/w % by total weight of composition.
 9. The pharmaceuticalcomposition of claim 8, wherein the pharmaceutically acceptableexcipient comprises: (a) a microcrystalline cellulose in the amount of30.0 to 35.0 w/w % by total weight of composition; (b) citric acidranging in the amount of 10.0 to 15.0 w/w % by total weight ofcomposition; (c) sodium bicarbonate in the amount of 13.0 to 17.0 w/w %by total weight of composition; (d) sodium lauryl sulfate in the amountof 3.0 to 8.0 w/w % by total weight of composition; (e) fumed silica inthe amount of 0.5 to 1.5 w/w % by total weight of composition; and (f)magnesium stearate in the amount of 0.5 to 1.5 w/w % by total weight ofcomposition.
 10. A method for attenuating or inhibiting the activity ofMnk in at least one cell overexpressing Mnk, comprising contacting theat least one cell with a compound according to claim 1 or astereoisomer, tautomer or solvate thereof.
 11. The method of claim 10,wherein the at least one cell is a colon cancer cell, a gastric cancercell, a thyroid cancer cell, a lung cancer cell, a leukemia cell, aB-cell lymphoma, a T-cell lymphoma, a hairy cell lymphoma, Hodgkin'slymphoma cell, non-Hodgkin's lymphoma cell, Burkitt's lymphoma cell, apancreatic cancer cell, a melanoma cell, a multiple melanoma cell, abrain cancer cell, a CNS cancer cell, a renal cancer cell, a prostatecancer cell, an ovarian cancer cell, or a breast cancer cell.
 12. Amethod for treating an Mnk dependent condition in a mammal in needthereof, comprising administering to the mammal a therapeuticallyeffective amount of at least one compound according to claim 1 or astereoisomer, tautomer, or solvate thereof.
 13. The method of claim 12,wherein the Mnk dependent condition is colorectal cancer, gastriccancer, thyroid cancer, lung cancer, leukemia, B-cell lymphoma, T-celllymphoma, hairy cell lymphoma, Hodgkin's lymphoma, non-Hodgkin'slymphoma, Burkitt's lymphoma, pancreatic cancer, melanoma, multiplemelanoma, brain cancer, CNS cancer, renal cancer, prostate cancer,ovarian cancer or breast cancer.
 14. The method of claim 13, wherein thecondition is B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma,non-Hodgkin's lymphoma, pancreatic cancer, melanoma, multiple melanoma,brain cancer, renal cancer, prostate cancer, ovarian cancer, and breastcancer.
 15. The method of claim 14, wherein the condition is B-celllymphoma, breast cancer, lung cancer, colorectal cancer, and prostatecancer.
 16. A method for treating an Mnk dependent condition in a mammalin need thereof, comprising administering to the mammal a pharmaceuticalcomposition of claim 4.